Note: Descriptions are shown in the official language in which they were submitted.
104'~00Z
~ his invention relates to new prostanoic acid
derivatives, and in particular it relates to new
prostanoic acid derivatives which are analogues of the
naturally occurring compounds known as prostaglandin F2a
and prostaglandin E2, showing a similar spectrum of
pharmacological properties and being useful for simi]ar
purposes. The relative potency of the new compounds,
however, in respect of the particular pharmacological
effects shown is different from that of the above
naturally occurring prostaglandins, and in particular
they are more potent as luteolytic agents than the
corresponding natural prostaglandins. That is to say,
the prostaglandin F2a analogues of the present invention
are more potent than natural prostaglandin F2a, and the
prostaglandin E2 analogues of the present invention are
more potent than natural prostaglandin E2. The new compounds
are, in a similar way, more potent as stimulants of
uterine smooth muscle than the corresponding natural
prostaglandins F2a and E2, and the prostaglandin E2
analogues of the invention are particularly valuable in
this respect. The new compounds are therefore advantageous
when used as contraceptives, for the termination of
pregnancy or for control of the oestrus cycle, and are
also useful for addition to semen intended for artificial
- 25 insemination of domestic animals~ the success rate of
insemination being thereby increased, especiall~ in pigs.
- 2 -
.
,. , . . ~ . : :
'' " ' : . ~ . ' ~' ' :.
- , :,
~: .
~: ,
1042002
Certain of the compounds are useful as vasodilators and bronchodilators, and
as inhibitors of platelet aggregation and of gastric secretion.
The cyclopentane derivatives described in this specification will
be named as derivatives of prostanoic acid of the formula shown below and
numbered as shown:^
: H
9 1 7 5 3 lCOOH
~~ .
10 ~ 20
11 ~ 13 15 17 19
H .
~ .
According to the invention there is provided a prostanoic acid
derivative of the formula:-
R~ ~ Rl I ~
; ' ' ' ' ;
. ,~ ~ A.CH(OH).R4
HO
; 10 wherein Rl i5 a carboxy radical or an alkoxycarbonyl radical of up to 11 .~;
` carbon atoms, A is an ethylene or trans-vinylene radical, and R4 is a phenyl, ~ -
'! naphthyl, furyl or 2-thienyl radical which is unsubstituted, or which is
substituted by one or two substituents selected from chlorine, fluorine,
. bromine and iodine atoms, and nitro, phenyl, chlorophenyl, methyl, ethyl,
. propyl, methoxy, ethoxy, methoxymethyl and trifluoromethyl radicals, R2 is
a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo
~- radical, which derivative optionally bears a 2-methyl substituent, and for
those compounds wherein Rl is a carboxy radical the pharmaceutically-and veter-
inarily-acceptable salts thereof.
.,. 20 A suitable value for Rl when it is an alkoxycarbonyl radical
is, for example, such a radical containing up to 11 carbon atoms, for example
the ~ethoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl radical. A
.
:-
, ~1 : .
-` 104ZOO;~
suitable value for A is, for example, the trans-vinylene or ethylene radical,
and a suitable value for R4 is a phenyl, naphthyl, 2- or 3-furyl or 2-thienyl
radical which, if substituted, preferably contains not more than 2 substituents
as defined above.
Suitable halogen substituents in the radical R4 are, for
example, fluorine, chlorine, bromine or iodine atoms; a suitable alkyl ;
substituent is, for example, a methyl, ethyl or propyl radical; a suitable
alkoxyalkyl substituent is, for example, the methoxymethyl, ethoxymethyl or
2-ethoxyethyl radical; a suitable halogenoalkyl radical is, for example, a
` 10 halogenomethyl radical; and suitable alkoxy, acylamino and dialkylamino
radicals, are, for example, the methoxy, ethoxy, acetamido and dimethylamino
radicals~ Thus, suitable values for R4 are phenyl, l-naphthyl, 2-naphthyl,
2-furyl, 3-furyl, 2-thienyl, fluorophenyl, chlorophenyl, bromophenyl,
iodophenyl, nitrophenyl, biphenylyl, chlorophenyl-2-furyl, tolyl, ethylphenyl,
propylphenyl, methoxymethylphenyl, ethoxymethylphenyl, (2-e~hoxyethyl) phenyl,
methoxyphenyl, ethoxyphenyl, halogenomethylphenyl, acetamidophenyl and
~'~ dimethylaminophenyl radicals.
~: 4
Particular values for R are the phenyl, 2-naphthyl, 2-furyl,
3-furyl, 2-thienyl, 4-fluorophenyl, 3- and 4-chlorophenyl, 3, 4-dichlorophenyl,
~ 20 4-nitrophenyl, 4-biphenylyl, 5-~4-chlorophenyl)-2-furyl, 4-tolyl, 4-methoxy-
- methylphenyl and 3- and 4-triflurormethylphenyl.
Examples of pharmaceutically- and veterinarily- acceptable
salts are the ammonium, alkylammonium containing
' '
, . .
- . ;.. -...... ~- ~
~04~00;~
1 to 4 alkyl~radicals each of 1 to 6 carbon atoms,
alkanolammonium containing 1 to 3 (2-hydroxyethyl) radicals
and alkali metal salts, for example the triethylammonium,
ethanolammonium, diethanolammonium, sodium and potassium
salts.
It will be observed that the compounds of the
formula I contain at least four asymmetric carbon atoms,
- namely carbon atoms 8, 11~ 12 and 15, the relative
configurations at three of which, 8, 11 and 12 are
10 specified in formula I, and that carbon atoms 2, 3, 4 and
9 may also be asymmetrically substituted, so that it is
clear that such compounds can exist in racemic form and
in at least two optically active forms. It is to be
understood that the useful properties of the racemate may
15 be present to differing extents in the optical isomers,
and that this invention relates to the racemic form of
the compounds of formula I and any optically active form
- which shows the above useful properties, it being a matter
of common general knowledge how the optically active forms
20 may be obtained, and to determine their respective
biological properties.
It is also to be understood that the above
definition encompasses both C-15 epimers and that in all
chemical formulae shown hereafter in this specification, the
25 same fixed stereochemistry at C-8, 11 and 12 as that shown
r~
. . . .. .. . .... . ~ . ~ . ....... .... ~ -
.. - . . . . -
~4ZOO;~
in formula I is implied.
A preferred group of prostanoic acid derivatives
of the invention comprises those compounds wherein R4
is the 3- or 4-chlorophenyl, 3,4-dichlorophenyl, 4-
nitrophenyl, 4-trifluoromethylphenyl or 4-methoxymethyl-
phenyl radical, and particularly preferred are those
compounds wherein R4 is the 4-chlorophenyl, 4-nitrophenyl
- or 4-trifluoromethylphenyl radical.
Of the C-15 epimers, those epimers which are
the more polar on silica gel thin la~er chromatography are
preferred to the less polar epimers in any pair.
Particular prostanoic acid derivatives of
the invention are described in the Examples, and particularly
preferred are 9a,11a,15-trihydroxy-15-(4-trifluoromethylphenyl)-
16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid,
15-(4-chlorophenyl)-9a,lla,15-trihydroxy-16,17,18,19,20-
pentanor-5-cis,13-trans-prostadienoic acid, methyl 15-
(4-chorophenyl)-9a,11a,15-trihydroxy-16,17,18,19,20-pentanor-
5-cis,13-trans-prostadienoate, 9a,11a,15-trihydroxy-15-
(4-nitrophenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-
prostadienoic acid, 15-(3-chlorophenyl)-9a,11a,15-trihydroxy-
16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid,
15-(3,4-dichlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19,20-
pentanor-5-cis,13-trans-prostadienoic acid and 9a,11a,15-
trihydroxy-15-(4-methoxymethylphenyl)-16,17,18,19~20-pentanor-
5-cis,13-trans-prosta~ienoic acid.
.
.
1042002
The cyclopentane derivatives of the invention may be manufactured :
by methods known in themselves for the manufacture of chemically analogous -
compounds. Thus, the following processes for the manufacture of the cyclopen-
tane derivatives of the formula I are provided as further features of the
invention~
~a) for those compounds wherein Rl is the carboxy radical, R2 is the hydroxy
radical, R3 is the hydrogen atom, the reaction of a lactol of the formula:-
f OH
O~\ .
\~\A-CH~oH).R4
HO
wherein A and R4 have the meanings stated above, with a C4-carboxybutyl)
triphenylphosphonium salt, optionally bearing a 2-methyl substituent , in
the presence of a strong base, whereafter when a salt is required the product
is reacted with a base; or
(b) for those compounds wherein Rl is an alkoxycarbonyl radical of 1 to 11
carbon atoms, the reaction of an acid of the formula:-
R2 R3 ~ :
CH2)3-COOH
III
~v~ A-CH(OH~.R4
HO
: : .
wherein A, R2, R3 and R4 have the meanings stated above, with a diazoalkane
: of 1 + 10 carbon atoms; or
(c) for those compounds wherein Rl is an alkoxycarbonyl radical of up to 11
carbon atoms, the reaction of a salt, for example the silver salt, of an
: acid of the formula III with an alkyl halide of 1 to 10 carbon atoms, for
example an alkyl iodide; or
t
:` `
104;~00Z
(d) the reduction of a compound of the formula:-
. R3 ~ -
R ~ ~ Rl :
~ `Co.R4 IV
- R7
wherein Rl, R and R4 have the meanings stated above, and R6 and R7 are each
a hydroxy radical or a protected hydroxy radical, and which optionally bears
a 2-methyl substituent, for example with zinc borohydride9 aluminium tri-
isopropoxide, or di-isobornyloxy aluminium isopropoxide, whereafter when R6
and R7 are each a protected hydroxy radical, the protecting groups are removed,
and if a salt is required, a carboxylic acid so obtained is reacted with a :~
base; or
~e) for those compounds wherein A is the trans-vinylene radical, the hydroly-
sis of a compound of the formula:- i-~. 3
R2 ~ ~ COOH V ;
~,J~ ., .
~ I ~ -fH.R4 ~ ~
R80 R8 ~ ~ ~
wherein R2, R3 and R4 have the meanings stated above, and R8 is an alkoxy-
dialkylmethyl radical of 4 to 8 carbon atoms for example the l-methoxy-l-
methylethyl radical; or
~; ~f) for those compounds wherein A is the ethylene radical, the hydrolysis of
a compound of the formula V wherein A, R2, R3 and R4 have the meanings stated
above and R8 is the tetrahydropyranyl radical, for example with aqueous acetic
acid or in an aqueous or alcoholic solution of an alkali metal carbonate, for
: 20 example potassium carbonate in methanol, at a temperature between ambient
temperature and about 60C.
,.~ ......
: - 8 -
1C~4Z002
A suitable protected hydroxy radical in process
(d) is, for example, an alkanoyloxy radical of up to 6 carbon atoms, for
example an acetoxy radical, or an aroyloxy radical of up to 12 carbon
atoms, for example a
~ 9 _
104ZOOZ
p-phenylbenzoyloxy radical.
The starting material of the ~ormula II wherein
A is the trans-vinylene radical which ma~ be used in the
process of the invention, may be obtained by reacting an
aldehyde VI (Ac = p-phenylbenzoyl) with a compound
(CH30)2P~o.~GH.CoR4 or a phosphorane Ph3P:CH.COR4 to give
an unsaturated ketone VII~ which is reduced to the enol
- VIII and hydrolysed to the diol IX. The lactone ring
is then reduced with di-isobutyl aluminium hydride to
give the required lactol starting material II. -
The starting material of the formula II wherein
A is an ethylene radical, used in the process of the
invention, may be obtained by hydrogenating an unsaturated
ketone VII in the presence of 5% palladium-on-carbon
catalyst, to give a saturated ketone, and repeating the
procedure outlined above using the saturated ketone in
place of an unsaturated ketone VII.
The starting material of the formula III wherein
R is an alkanoyloxy radical may be obtained from the
corresponding compound wherein R2 is a hydroxy radical by
acylation with an acid anhydride in pyridine to give a
9-ester-1-mixed ~anhydride, which may be hydrolysed to the
required starting material.
The starting material of the formula I~ may be
obtained from the known compound 4~-dimethoxymethyl-2,3,3a~,
~r
. . . - ~
.... - ~: , . . : -
lO~ZOOZ
o ~o/
o,-~ o~
CHO ~ CO . R
AcO AcO
VI VI I
O O
o~
- ~ \~\~CH(oH).R4 ~H(oH).R4
AcO
HO
VIII IX
> I I
Ac represents an acyl radical.
'
.
rA~
'
, . . . . . . ~ ~
10~;200;~ .
6a~-tetrahydro-5~-hydroxy-6~-iodo-2-oxocyclopenteno
[b~furan (X) by ~reatment with tribut~l tin hydride to
give the de-iodinated lactone XI. The 5a-hydroxy group
is protected as the tetrahydropyran-2-yl ether XII, the
lactone is reduced to the lactol XIII, using di-isobutyl
alumium hydride, and the lactol is reacted with (4-
carboxy-butyl) triphenylphosphonium bromide to give the
cylopentanol derivative XIV, which after esterification,
protection of the two hydroxyl group as p-phenylbenzoate
esters,hydrolysis of the acetal~reaction with a
phosphonate of the formula (CH30)2Po.CH2CoR4 in the
presence of a strong base,and methanolysis of the
tetrahydropyranyl group gives a starting material of the
formula IV (Rl = methoxycarbonyl, R6 = R7 = hydroxy).
The star$ing material of the formula ~ may be
obtained from the corresponding intermediate of the
formula IX by reaction thereof with 2-methoxypropene to
give a bis-ketal, which is converted by di-isobutyl
aluminium hydride reduction and reaction with (4-carboxybutyl)-
triphenylphosphonium bromide as described above, to a
starting material V (R2 = hydroxy, R3 = hydrogen),
which in turn may be oxidised with chromium trioxide to
the corresponding starting material V (R2 and ~3 together
are oxo).
The starting material of the formula V, wherein
., .
-. . .: : ,
.
~, ' .
lO~ZQO'~
,o
~ ?
- I ~ ~ ClI(OCI13)2 ~ CH(OCH3)2
HO . Hd
. XT DH
X
~ CH(OCH~ CH(ocH~)2
THP.O THP.O
XII XIII
.
~ ~ ~ ~ COOH
~ ~ I .
~ CH(OCH3)2 ~~ ~ IV
THP.O
XIV
THP ~ tetrahydropyran-2-yl.
.
,, ' ~, ', : ' ' .
-, ~' ,: ', .. ' . -
104200'~
R8 is the tetrahydropyranyl radical~ used in process (g),
may be obtained by reacting the diol fX with 2,3-dihydropyran
to give the bis-ether, followed by reduction to the lactol
and reaction thereof with (4-carboxybutyl)triphenyl-
phosphonium bromide in the presence of a strong base, asdescribed above~
As stated above, the compounds of the invention
possess a profile of pharmacological properties which
differs from that of the naturally occurring prostaglandins
F2a and E2. Thus, for example the more polar C-15 epimer
of l-(4-chlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19,20-
pentanor-5-cis,13-trans-prostadienoic acid is at least
50 times as active as prostaglandin F2~ as a luteolytic
agent, yet has only approximately the same smooth muscle
stimulant activity as prostaglandin F2a.
When a compound of the invention is to be used,
for example for the induction of labour, it is used in --
the same way as it is known to use the naturally-occurring
prostaglandins E2 and F2a, that is to say, by administering
a sterile, substantially aqueous solution containing up to
lmg./ml. of active compound, by intravenous i.nfusion~by
transcervical extra-ammotic injection,or by intra-ammotic
injection,until labour commences.
Thus, according to a further feature of the
invention there is provided aPharmaceutical or veterinary
composition comprising a prostanoic acid derivative of the
)~
_ ~ _
- . . . ~
- - - ,
.. . :
- .
10420Q~
invention, together With a pharmaceutically- or
veterinarily- acceptable diluent or carrier
The compositionsmay be in a form suitable for
oral administration,for example tablets or capsules, in
a form suitable for inhalation, for example an aerosol,
or a solution suitable for spraying, in a form suitable
for intra-uterine infusion or parenteral administration
for example a sterile, substantially aqueous solution,
or in the form of a suppository, suitable for anal or
vaginal use. As stated above, when the compound of the
invention is to be used for the induction of labour in
childbirth, a preferred composition of the invention is
a sterile, substantially aqueous, solution.
The compositions of the invention may be
prepared by conventional means, and may incorporate
conventional excipients.
The invention is illustrated, but not limited
by the following Examples. RF values refer to thin
layer chromatography on Merck silica gel, unless otherwise
` 20 stated.
Example 1
Finely powdered (4-carboxybutyl)triphenylphosphonium
bromide (0 532 g.) was heated to 100C. under vacuum for
1 h~ur. The evacuated reaction vessel was filled with an
~ 25 atmosphere of dry nitrogen~ the solid was dissolved in
: :
. 1
.: ~, _ ~ _
,~
:
.. . :
.. , . ~ , . - . .. .
. : - . . . . : : . .
: :. . -: - .~: -
104Z00~
dimethylsulphoxide (2 ml.~ and the solution was cooled ~n
room temperature ~o this solution was added dropwise
1.1 ml. of a 2M solution of methanesulphinylmethyl sodium
in dimethyl sulphoxide followed by a solution of the
mixture of epimers of 4~-(3-p-chlorophenyl-3-hydroxy-1-
trans-propenyl)-2,3,3a~,6a~-tetrahydro-2,5a-
dihydroxycyclopenteno[b]furan (72 mg.) in a mixture of
dimethylsulphoxide (2 ml.) and benzene (0.3ml.). The
solution was stirred for 3 hours, and the solvent was
removed by evaporation under reduced pressure at a
temperature below 40C. ~he residue was shaken with
water (10 ml.) and ethyl acetate (10 ml.) and the aqueous
phase was separated, extracted with ethyl acetate (2 x
10 ml.) and the extracts discarded. The aqueous solution
was acidified to pH 3-4 with 2N aqueous oxalic acid, and
extracted with a mixture of equal parts of ether and
petroleum ether (b.p. 40-60C.) (5 x 10 ml.). The
organic phase was separated, washed with saturated brine
; and was dried. Evaporation of the solvents gave a
mixture of the C-15 epimers of 9a,11~,15-trihydroxy-15-
'~ (4-chlorophenyl)-16,17,18,19"20-pentanor-5-cis,13-trans-
pro~adienoic acid. Thin layer chromatography, ùsing 3%
acetic acid in ethyl acetate, separated the C-15 epimers,
having RF values of 0.3 and 0~4 respectively. The
n,m.r. spectrum of each isomer (in deuterated acetone)
~, .
/6
.- ~
, . .
1042002
showed the follo~Ting characteristic bands (~ values):-
7,35, doublet, 4 aromatic protons
5 1 - 5.6, 4 olefinic protons.
The mass spectrum of the tetra(trimethylsilyl)derivative
showed M = 682.3410 (calculated 682.3129).
The cyclopenteno[b]furan used as starting
material may be obtained as follows:-
n-Butyl-lithium (39 ml. of a 2.2M solution in hexane)
was added to a solution of dimethyl methylphosphonate
(11.3 g.) in dry tetrahydrofuran at -78C. in an atmosphere
of nitrogen. After 10 minutes, a solution of ethyl 4-
chlorobenzoate (8.o g.) in dry tetrahydrofuran (20 ml.)
was added dropwise, and the mixture was stirred for
4 hours at -78C. The reaction mixture was neutralised
with acetic acid and the solvents were removed under
reduced pressure. The Pesidue was shaken with a mixture ~-
of ethyl acetate (100 ml.) and water (20 ml,), and the
organic phase was separated and washed with brine. The
solution was dried, the solvents were evaporated and the
residue was distilled in a bulb distillation apparatus at -
an oven temperature of 210C. and 0.1 mm. pressure, to
give dimethyl 2-(~chlorophenyl)æ-oxoethylphosphonate.
A solution of dimethyl 2-(4-chlorophenyl)-2-
oxoethylphosphonate (2.36g.) in dry 1,2-dimethoxyethane
(40 ml.) at -78C. was treated with n-butyl-lithium
,~ _ ~_ , .
: : :: ~ . .: : ~, .
,, ::, :, . : :
104~:00;~
(5.6 ml. of a 1.4~ solution in hexane), and the mixture
was stirred for 15 minutes. To this mixture was added
a solution of 4~-formyl-2,3,3aB,6a~-tetrahydro-2-oxo-5a-
(4-phenylbenzoyloxy)cyclopenteno[b]furan (2.1 g.) in 1,2-
dimethoxyethane (10 ml.), and after 1 hour the reaction
mixture was neutralised with glacial acetic acid and all ~ -
solvents were removed by evaporation under reduced pressure
below 35C. The residue was triturated with ether to
yield the unsaturated ketone product, as a white solid,
RF = 0.6, (50~ ethyl acetate in toluene),
The unsaturated ketone (1.5 g.) was dissolved in
dry benzene (50 ml.) and to the solution was added 11 ml.
of a 0.515M solution of aluminium isopropoxide in benzene.
The mixture was stirred under reflux for 2 hours, then
saturated sodium hydrogen tartrate solution was added.
Ethyl acetate (200 ml.) was added, the organic layer was
separated, washed with a 1:1 mixture of saturated brine and
water, thendried. The solvents were evaporated to give
a mixture of epimeric unsaturated alcohols, RF = 0 2 (50%
ethyl acetate in toluene).
The mixture of epimeric unsaturated alcohols
(1.5 g.) was stirred vigorously for 2 hours with finely
powdered anhydrous potassium carbonate (427 mg.) in
methanol (20 ml.). lN Hydrochloric acid (6 .o8 ml.) was
added, followed by ethyl acetate (100 ml.). The organic
- ' ' - '
.
:
'' ' ~
~-
104ZOOZ
layer was separated, washed successively with saturated
sodium bicarbonate solution and saturated brine, and
dried, and the solvents were evaporated. The residue
was chromatographed on Florisil (20 g.). Elution with
ether removed by-products, and subsequent elution with
ethyl acetate gave a mixture of the C-15 epimeric diols,
RF = -3 (ethyl acetate).
; To a solution of the epimeric diols (369 mg.)
in dry toluene (5 ml.) under an atmosphere of nitrogen
at -78C. was added 0.5 ml. of a 2.2 m mole/ml. solution
of di-isobutyl aluminium hydride in toluene. After
30 minutes the reaction was quenched by the dropwise
addition of methanol(3 ml.) and after a further 15 minutes
at room temperature a mixture of 1:1 saturated brine/water ~
(25 ml.) was added, and the mixture was extracted with --
ethyl acetate (3 x 50 ml.~. The extract was washed with
saturated brine, and dried, and the solvents were evaporated
to give a mixture of epimers of 4~-(3-p-chlorophenyl-3-
hydroxy-l-trans-propenyl)-2,3~3a~,6a~-tetrahydro-2,5a-
dihydroxycyclopenteno[b]furan, RF = -3 (2~ methanol in
ethylacetate).
Example 2
The process described in Example 1 was repeated
using the appropriate cyclopenteno[b~furan to give the ~;~
compounds shown in the Table below. MaEs spectrum
~ ~rade Mc~rk
.
,. . . ~ .
:. - . ~. , :
~ . . :
104'~002
measurements refer to the tetra-(trimethylsilyl) derivatives.
Characterising data for the phosphonate reagents
(CH30)2 Po.CH2CoR4 and for the enones ~II (Ac = p-
phenylbenzoyl) are also shown:-
HO~ H 2
~ ,- \ ~ ~ COOH
,~ ~ CH(OH) ~
HO 9
R
. . . - - ,. ,.
No. R9Other substituent in
prostanoic acid
. . ,
1 3-chloro
2 4-chloro _
3 4-fluoro _
4 ; 4-methyl _
3-trifluoromethyl _
6 4-trifluoromethyl _
7 4-trifluoromethyl2-methyl
_ . ~ .... . .
r--~ . .. __ .
No. Mass Spectrum Phosphonate Enone
. b.p. C./mm Hg.
Found Calculate d
_ ~ ~
1M+=682.3095682.3129 RF = 0.2 a)m.p.l63-164G.
2M+=682.3140682.3129 210/0.1RF = 0.65 b)
3M+=666.3387666.3425 RF = 0.3 c)m.p.l29-130C.
4M+=662.3669662.3670 210/0.1m.p.170-176C.
570~.3126 701.3159 RF = 0.3 a )RF = 6 b
6"=701.3133701.3159 140/0.4m.p.178 C.
7M+=730.351173.3549 _
r-
... . - . .
. . . ~ . . 1 ~
-
;. .
:; .~
.
1042002
a) in 50% ethyl acetate/chloroform.
b) in 50% ethyl acetate,!toluene.
c) in 75% ethyl acetate/methylene dichloride.
For No.2, the mass spectrum data refer to each
C-15 epimer, for Nos. 1 and 3 to 8, the data refer
to the mixed C-15 epimers. -
Example 3
,
Methyl 15-(4-methoxymethylphenyl)-15-oxo-9,
lla-di-(4-phenylbenzoyloxy)-5-cis,13-trans-prostadienoate
(110 mg.) was stirred in dry toluene (5.0 ml.) under argon
at room temperature, and treated with a 0.323M solution
of di-isobornyloxyaluminium isopropoxide in toluene (2.Oml.).
After 1~ hours, the mixture was partitioned between water
(0.5 ml.) and ethyl acetate (1 0 ml.), and filtered through
'Hyflo,' washing the filter pad with ethyl acetate (2 x 4ml.).
The organic layer was separated, washed with brine (4ml.),
dried over magnesium sulphate and filtered, and the solvent
was evaporated to leave a crude oily product, which was
chromatographed on 'Florisil~ (2g.). Elution with 5-10%
ethyl acetate in toluene gave the enol, methyl 15-hydroxy-
15-(4-methoxymethylphenyl)-9a,11a-di-(4-phenylbenzoyloxy)-
5-cis,13-trans-prostadienoate as a viscous oil, RF = 4
(20% ethyl acetate in methylene dichloride)
The crude enol (69 mg.) was stirred under
argon in a mixture of methanol (4 ml.), water (0.7 ml.) and
N potassium hydroxide (0.9 ml.) for 18 hrs. The mixture
Trqde l~ rk
:. .- . . ~ ~ . -
: . ~
104200~
was acidified to pH 5 with oxalic acid, and extracted
with ethvl acetate, the extracts were washed with 1:1
saturated brine/water, and dried. Evaporation of the
solvents gave a residue, from which the two C-15 epimers
were separated by thin layer chromatography, using 3%
acetic acid in ethyl acetate, RF = 3 and 0.4. The
n.m.r. spectrum of each epimer in deuterated acetone
- showed the following characteristic peaks (~ values):-
7.2-7,4, 4H, aromatic.
105.1-5.6, 5H, 4 olefinic protons and -CH(OH).CH=CH-
4.4, 2H, -CH2.OMe
3.32, 3H, -CH2.OMe
The mass spectrum showed (M-CH3) = 677.3493, calculated
for C35H6406Si4 = 677.3547 (for the tetra-trimethvlsilyl deriv~tive).
15The methyl 15-(4-methoxymethylphenyl)-15-oxo-
9~,11a-di-(4-phenylbenzoyloxy)-5-cis,13-tra:ns-prostadienoate
; used as starting material in the above process may be
obtained as follows:-
4~-Dimethoxymethyl-2,3,3a~,6a~-tetrahydro-5~-
hydroxy-6~-iodo-2-oxocyclopenteno[b~furan (4.0g.) in dry
toluene (40ml.) was stirred under argon at 80C. with
tri-n-butyl tin hydride (6.6g.) for 18 hours. The solvent
was evaporated under reduced pressure and the residue was
stirred with pe~roleum ether (b.p. 40-60C., lOOml.) for
3 minutes The solvent was decanted and the residual
':
r~ ~
.
.
104Z00;~ ;
~A~ oil was chromatographed on ~Florisil~ (50g~). Elution
with mixtures containing 25% ethyl acetate in toluene
and finally with ethyl acetate gave 4~dimethoxymethyl-
2,3,3a~,6a~~tetrahydro-5a-hydroxy-2-oxocyclopenteno [blfuran
5 as an oil, RF = 3 (20% acetone in chloroform). The
n.m.r. spectrum in deuteriochloroform showed the following
characteristic peaks (S values):-
3.40 and 3.42, 6H, 2 singlets, methoxy
4.04-4.36 f lH, multiplet 5~ proton
10li lH, doublet, -CH(OMe)2
lH, multiplet, 6a~ proton
4~-Dimethoxymethyl-2,3,3a~,6a~-tetrahvdro-5~-
- hydroxy-2-oxoc~Tclopenteno[b~furan (4.01g ) was stirred
under argon in dry toluene (30ml.), and the resulting
15 solution was treated with an excess of freshly distilled
dihydropyran (17 ml.), followed bv 2.0 ml, of a 0.1%w/v
solution of toluene-p-sulphonic acid in drv tetrahydrofuran.
After 3/4 hour, the mixture was treated with pyridine
(0.50ml.) and then partitioned between ethyl acetate tl50ml.)
20 and saturated sodium bicarbonate (75ml.). The organic
layer was separated, washed with saturated brine (50ml.),
dried over magnesium sulphate and filtered, and the solvent
was evaporated to give a crude lactone, 4~-dimethoxyvmeth~l-
2,3,3a~,6a~-tetrahydro-2-oxo-5~-(tetrahydropyran-2-yloxy)-
25 cyclopenteno[b]furan, RF = -7 (20% acetone in chloroform).
The crude lactone (6.2g ) was dissolved by
~_ ~23
TrRde, n;~O~f~
. . . -', .' ' ., . ,
- , . . . .
. .
- . . ,, ~ .
~04ZOO;~
stirring in dry dimethoxyethane (120ml.) under argon at
~! about -60C~ (chloroform ~ 'Dr~kold' cooling bath),
and 1.7~ di-isobutylaluminium hydride (11.2M) was
added. After 30 minutes, methanol (3ml~) was added,
the mixture was allowed to warm up to room temperature,
and was partitioned between ethyl acetate (600ml.) and
1:1 saturated brine~water (300ml.). The whole mixture
was filtered through 'Hyrlo' and the two phases were
separated. The aqueous phase was re-extracted with
ethyl acetate (300ml.) and the combined organic layers
were washed with water (lOOml.), dried over magnesium
sulphate and filtered, and the solvents were evaporated
to give the crude lactol (VI) 4~-dimethoxymethyl-2,3,3a~,6a~-
tetrahydro-2-hydroxy-5~-(tetrahydropyran-2-yloxy)-
cyclopenteno[b]furan, as an oil, RF = -4 (20% acetone in
chloroform).
A stirred solution of (4-carboxybutyl)triphenyl-
phosphonium bromide (24 8g.) in dry dimethylsulphoxide
(DMSO, 50ml.) was treated slowly under argon and with
cooling in an ice-water bath, with 2M methanesulphinylmethyl
sodium in DMSO (54.5ml~, 2.5 equivalents) to form a
solution of the corresponding ylide. The crude lactol
(6.3g.) in dry DMSO (150ml.) was then added to the ylide
solution at room temperature, The mixture was stirred for
11 hours, then water (lml.) was added. The DMSO was then
2~
~ -
Tr~de ~ rk
. - . . . . ~ ~... . . :
... ~ - .
. , . ;: . . ~: . ~ . :
. ... : .
.. -, : .
lO~ZOOZ
evaporated at high Vacuum at a temperature not exceeding
50C The resldual gum was partitioned between ether
(4 x 225ml.) and water (150ml.). The aqueous layer
was separated, acidified with 2N oxalic acid to approximately
pH 4, and then extracted with 1;1 mixture of ether and
pentane (3 x 300ml )~ The extracts were washed with
saturated brine (150ml.) dried over magnesium sulphate
- and filtered, and the solvent was evaporated to give the
crude acid, 2~-dimethoxy_methyl-5a-hydroxy-3a-
10 (tetrahydropyran-2-yloxv)cYclopent-la-ylhept-5-cis-enoic
acid as an oil, suitable for use in the next stage of
the synthesis. A sample was ~urified by chromatography
on silica (70:1) eluting the product with 2% methanol in
toluene as an oil, RF = -4 (5% methanol in meth~lene
chloride). The n.m~r spectrum in deuteriochloroform
showed the following characteristic peaks (~ values):-
3.35, 6H, singlet, methoxy
3.3-3.65, lH,
3.68-4.o, lH, ~
4.00-4.19, 2H,~ multiplets, ~CH-0-
4.19-4,38, lH,
- 4.6-4.8, lH,
5.09-5 78, 2H, multiplet, olefinic protons
The crude acid (4,48~ ) in methanol (45ml.~ was
stirred under argon at room temperature with toluene-p-
sulphonic acid (240mg,) for 23/4 hours The solution was
~5
-
104~002
then partitioned between ethyl acetate (300ml.~ and
saturated sodium bicarbonate (60ml.) followed by saturated
brine (60ml.), The organic phase was dried over
magnesium sulphate and filtered, and the solvent was
evaporated to leave a crude ester-diol, methyl 2~-
dimethoxymethyl-3~,5~-dihydroxycyclopent-1~-ylhept-5-
cis-enoate as an oil, RF = o.65 (10% methanol in methylene
chloride). The n.m.r. spectrum in deuteriochloroform
showed the ~ollowing principal peaks (~ values):-
3.39, 6H, singlet~~
3.64, 3H, singlet 3 3 methyl groups
4,03-4.3, 3H, ( multiplet, ~CH-0-
¦ doublet, ~CH(OMe)2
5.1-5.7, 2H, multiplet, olefinic protons
The crude ester-diol (3.3g~) was dissolved in
dry pyridine (50ml.) under argon, and treated with
p-phenylbenzoyl chloride (9.2g.) and the mixture was
stirred for 17 hours. Water (0,8ml ) was then introduced
and stirring was continued for 3-4 hours. The mixture was
evaporated under reduced pressure and toluene was added to
assist azeotropic removal of the pyridine The residue
was partitioned between toluene (300ml.) and saturated
sodium bicarbonate solution (150ml.), The whole mixture
was filtered through 'Hyflo~ and the organic phase was
separated. The aqueous layer was extracted with toluene
~G
T~ dQ ll/lo~rk - ~
: . , . . - .
.
~04200~
(150ml.), and the organic extracts were combined, washed
with brine (lOOml.), dried over magnesium sulphate,
and filtered, and the solvent was evaporated to leave a
solid crystalline residue This was thoroughly triturated
with methanol (70ml.), the mixture was filtered, and the
product was washed with more methanol (3 x lOml ) to give
the dimethylacetal, methyl 2~-dimethoxymethyl-3a,5a-di-
(4-phenylbenzoyloxy)cyclopent-la-ylhept-5-cis-enoate as
a white solid, m.p 104.5-106.5C., RF = 5 (5% acetone
in toluene). The n.m.r. spectrum in deuteriochloroform
showed the following characteristic signals (~ values):-
3.41, 3H, singlet 1
3.47, 3H, singlet ~ methyls
3.52, 3H, singlet
4.59-4.61, lH doublet, ,CH(OMe)2
5.17-5.70, 4H, multiplet, 2 x ~CH-O- and 2 olefinic protons
7.80-8.00, 2H,~ H
ldoublet ~ G~ CO 0-
8.oo-8.20, 2H,~
An analytical sample recrystallised three times
from ethanol had m.p. 105-107C.
Methyl 2~-dimethoxymethyl-3~,5a-di-(4-phenyl-
benzoyloxy)-cyclopent-la-ylhept-5- CiS -enoate (500mg.)
was vigorously stirred under argon for 10 minutes in a two-
phase system consisting of 2% isopropanol in chloroform (20ml.)
and concentrated hydrochloric acid (lOml~) The chloroform
~ ~: , - - ., : -. ;
,. - ... , . ~ . . . . . .. ... .. . .
.
~04ZOUZ
layer was separated and the aqueous layer was extracted
- with chloroform (20ml.). The organic layers were combined,
washed successively with aqueous saturated sodium
bicarbonate (20ml.) and saturated brine (lOml.), dried
over magnesium sulphate and filtered, and the solvent was
evaporated. The oily residue crystallised on drying under
high vacuum to give methyl 2~-formyl-3a,5a-di-(4-
phenylbenzoyloxy)cyclopent-la-ylhept-5-cis-enoate, RF on
Merck silica gel GF 254 plates was 0.4 (5% ethyl acetate
in toluene). The n m.r. spectrum in deuteriochloroform
was consistent with the required structure, and showed the -
following principal signals (~ values):-
3.51, 3H, singlet, methyl ester.
5,3-5.6, 4H, multiplet, ,CH-O- and olefinic protons.
7.8-8.o, 2H,~ H
8.0_8 2 2H 3 dOubletS ~co. o -
7 22-7 73, 14H, multiplet, rest of aromatic protons
10.01-10 14, lH, doublet, -CHO
An analytical sample, m.p. 93-97C., was obtained
by triturating the above-described product with ether.
A solution of dimethyl 2-(4-methoxymethylphenyl)-
2-oxo-phosphonate (104 mg 1.5 equivalent) in tetrahydrofuran
(3.0ml.) was stirred under argon and cooled in a
A chloroform/'Drikold' bath, and treated with 2.2M butyl-
lithium in hexane (148 ~1.) followed after a few minutes
"~ _ ~g _
Irqde ~ Q ~k
, . . . ~ . . i . . ,
. - . - . . . . , i . ~.~ ... .:: . . . ...
- . ~ . . . , ;.; ... . . ;: ., . ... , -~ . - . . -
.. . . ..... : .. ~ .. ~ . ~ .... . .
- `
104200Z
by a solution of methyl 2~-dimethoxymethvl-3a,5a-di-(4-
phenylbenzoyloxy)cyclopent-la-ylhept-5-cis-enoate (157mg.),
also in tetrahydrofuran (2~0ml~) The cooling bath was
then removed, and after 2 hours a few drops of acetic acid
and then water (200~1~) were added to adjust the pH to
about 6. The solvent was evaporated under reduced
pressure and the residue was partitioned between water
(15ml.) and ethyl acetate (1 x 30ml., 1 x 15ml.). The
organic layer was separated, washed with water (lOml.)
then dried over magnesium sulphate, and filtered, and
the solvent was evaporated to give a viscous oil. This
~Al oil was purified by chromatography on 'Florisil~
(2g.) eluting with 10% ethyl acetate in toluene to afford
the required enone starting material, methyl 15-(4-
methoxymethylphenyl)-15-oxo-9a,11a-di-(4-phenylbenzoyloxy)-
5-cis,13-trans-prostadienoate, as an oil, RF = -4 (20%
ethyl acetate in methylene dichloride). The n.m.r.
spectrum in deuteriochloroform showed the following
principal peaks (~ values)--
3.35, 3H, singlet, methoxy.
3 50, 3H, singlet, -COOCH3.
4 45, 2H, -CH20CH3.
5.4-5.6, 4H, multiplet, cis olefinic protons and ,CH-O-
6.12-7.1, lH, doublet, =CH.CO-
7.86-8.02, 2H, doublet ) ~ COO-
8 02-8.23, 2H, doublet
~r~ C
.
.
- ~
- ~ . . .
1042002
7.3-7.7, 15H, multiplet, rest of aromatic protons
+ -CH=CH.C0-
Example 4
The process described in Example 3 was repeated,
using the appropriate enone, to give the compounds shown
in the Table below. Mass spectrum measurements refer to
the tetra-(trimethylsilyl) derivatives. Characterising
data are given also for the phosphonate reagents
(CH30)2Po.CH2CoR4 and for the enone starting materials:-
H0~ ~H
~ ' C2H
~ CH(oH).R4
; H0
No, _ ~_ _ 3~cct . ~
Found Calculated
~ - __~ ... .. ~
1 phenyl M =648.3462 648.3462
2 2-chlorophenyl (M-CH3) =667.2829 667.2895
3 3,4-dichlorophenyl m.p.,M+=716.2722 716.2746
l.p.,M =716
4 4-nitrophenyl (M -CH3~678.3144 678.3136
4-biphenylyl M+=724.3831 724.3832
6 2-naphthyl M =698.3620 698.3676
7 2-furyl M+=638.3252 638.3312
8 5-p-chlorophenyl-2-furyl M+=748.3201 748.3235
9 3-furyl M+=638.3303 638.3312
2-thienyl m.p.,654.3045 654,3084
l.p.,654
-- ~ 7- ' ~~' ~ - --~---.- . __
r~ - ~ -
- . - . . .~ . . .
104Z00~
_ ~ ~
No. Phosphonate Enone
_ . , .. ~ ~_
1 b.p.162C /O.lmm.Hg, RF=0 7,ethylacetate/
toluene
2 b p,185C /0 05mm.Hg. a)
3 RF=0.3,ethylacetate . m.p.107-109C,
4 m p.73-75C RF=0,8,50%ethylacetate/
toluene
m.p,85-87C RF=0.77~ether,
6 b.p 240C./0 5mm.Hg. RF=0.93,ether.
7 b p 150C /O.lmm.Hg RF=0.76,ether.
8 RF=0,22,ethylacetate RF=0,81,ether.
9 b p.150C./O.lmm.Hg, RF=0 82,ether.
RF=0.19,50% ethylacetate/ RF=0.79,ether. -
methylene dichloride
~_ _ . , _, ~ ~_
a) Mass spectrum gave (M-phenylbenzoyl) = 568.1973,
calculated from C35H3305C1 568.
~ ..
.,
To a solution of a mixture of the C-15 epimers
of 15-(4-chlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19,
20-pentanor-5-cis,13-trans-prostadienoic acid (12mg ) in
methanol (1 ml.) at 0C. was added an excess of a solution
of diazomethane in ether. After 10 minutes, the solvents
~were evaporated to give a mixture of the C-15 epimers of
methyl 15-(4-chlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19
20-pentanor-5-cis,13-trans-prostadienate as a clear oil,
RF = -3 and 0.4 (ethyl acetate). For the more polar
_ 3~_
',: .......... . .:.~' ' . '` -
t .. ' ~ '
104'~00;~
epimer, the tris-(trimethylsilyl)derivative showed M
624.2840, calculated for C31H53C105Si3 = 624.2889
Exam~le 6
A solution of 15-(4-chlorophenyl)-9a-hydroxy-
lla,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-
pentanor-5-cis-prostenoic acid (270mg.) in 3 ml of a
2:1 mixture of acetic acid and water, was stirred at
50C. for 4 hours. The solvents were evaporated~ the
residue was dissolved in dilute aqueous sodium bicarbonate -~
solution (2 ml.) and the solution was extracted with
ethyl acetate (3 x 2 ml.) and the extracts were discarded.
The aqueous solution was acidifi~dto pH 3-4 with 2N
aqueous oxalic acid and the acidified solution was -
extracted with ethyl acetate (4 x 5 ml.). The ethyl
acetate extracts were washed with a 1:1 mixture of
saturated brine and water, and were then dried. After
evaporation of the ethyl acetate, the residue consisted
of a mixture of the C-15 epimers of 15-(4-chlorophenyl)-
9a,11~,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,
20 prostenoic acid. The mass spectrum of the tetra-(trimethylsilyl)
derivative gave (M-CH3) = 669.3031, calculated for
C32H58C105Si4 = 669.3051.
The bis-tetrahydropyranyl ether used as starting
material in the above reaction may be obtained as follows:~
5% Palladium-on-charcoal (300mg.) was added to
a solution of 4~-[3-(4-chlorophenyl)-3-oxo-1-trans-propenyl]-
.. , , .: . .... . -
: ' :. - ' ': ' - -. ,~. . ~ .~ , ,,
104'~Z
2,3,3a~,6a~-tetrahydro-2-oxo-5a-(4-phenylbenzoyloxy)
cyclopenteno[b]furan (974mg.) (the unsaturated ketone
described in the second part of Example 1) in chloroform
(15ml.), and the mixture was shaken in an atmosphe~ of
hydrogen for 20 minutes. The mixture was filtered, and
the filtrate evaporated to dryness to give the saturated
ketone 4~-[3-(4-chlorophenyl)-3-oxopropyl~-2,3,3a~,6a~-
tetrahydro-2-oxo-5-(4-phenylbenzoyloxy)cyclopenteno[b~furan ,
RF = -3 (5% ethyl acetate in toluene).
The remainder of the process described in the
second part of Example 1 was repeated, using this
saturated ketone in place of the unsaturated ketone to give
successively mixed epimeric alcohols, and mixed epimeric
diols, which were converted in conventional manner to
epimeric bis-(tetrahydropyran-2-yl) ethers with 2,3-
dihydropyran in tetrahydrofuran in the presence of toluene-
p-sulphonic acid. The lactone ring in the bis-ether was
reduced to the corresponding lactol in conventional manner
using di-isobutyl aluminium hydride in toluene, and the
lactol was reacted in conventional manner with (4-carboxybutyl)-
triphenylphosphonium bromide in dimethylsulphoxide in the
; presence of methanesulphinylmethyl sodium to give the
required bis-(tetrahydropyranyl) ether starting material~
15-(4-chlorophenyl)-9~-hydroxy-11~15-bis-(tetrahydropyran-
2-yloxy)-16,17,18,19,20-pentanor-5-cis-prostenoic acid.
r
33
-- - ~ .
lO~Z002
Example 7
....... . .. . .
The process described in Example 6 was repeated
using 15-(4-chlorophenyl)-9-oxo-11~i,15-bis-(tetrahydropyran-
2-yloxy)-16,17,18319,20-pentanor-5-cis-prostanoic acid in
place of the corresponding 9~-hvdroxy compound, to give
15-(4-chlorophenyl)-11~i,15-dihydroxy-9-oxo-16,17,18,19,20-
pentanor-5-cis-prostenoic acid, RF = -4 (3% acetic acid
in ethyl acetate). The mass spectrum of the bis-
trimethylsilyl-9-methoxime methyl ester showed r~+ = 581.2745,
calculated for C29H48ClN05Si2 = 581-2759
The bis-(tetrahydropyranyl)ether used as starting
material may be obtained by oxidation of the corresponding
9a-hydroxy-bis-ether, described in the second part of
Example 6, as follows:-
To a solution of 15-(4-chlorophenyl)-9a-hydroxy-
~ lla,15-bis-(tetrahydropyran-2-yloxy)-16,17,18,19,20-
pentanor-5--cis-prostenoic acid (lOOmg.) in acetone (2 ml.)
at -10C. was added Jones' reagent (0.06ml.). After
15 minutes, isopropanol (1 drop) was added, followed by
ethyl acetate (lOml.). The solution was washed with 1:1
brine/water, and was dried. Evaporation of the solvents,
and chromatography of the residue on silica, using 1:1
ether/petroleum ether (b,p. 40-60C,) as eluting solvent,
gave the required 9-oxo-bis-ether starting material, RF =
0.2 (50% ethyl acetate in toluene). -~
Example 8
A solution of 15-(4-chlorophenyl)-lla~15-bis-
~ ., . ~ .,, . . - .
104ZOOZ
(l-methoxy-l-methylethoxy)-9-oxo-16,17,18,19,20-pentanor-
5-c ,13-trans-prostadienoic acid (50mg.) in 0.25ml. of
pH 3 citric acid buffer and 0 75 ml. of acetone was
stirred at room temperature for 18 hours The solvents
were evaporated and the residue wàs extracted with ethyl
acetate (3 x 2 mls~). The extracts were washed with a
1:1 mixture of saturated brine and water, and were then
dried. After evaporation of theethyl acetate, the
residue consisted of a mixture of the C-15 epimers of
15-(4-chlorophenyl)-11~,15-dihydroxy-9-oxo-16,17,18,19~20-
pentanor-5-cis,13-trans-prostadienoic acid. Chromatography
of this residue on CC4 Malinkrodt silica gel (2g.), and
elution with ethyl acetate/cyclohexane gave the separated
C-15 epimers of 15-(4-chlorophenyl)-11~,15-dihydroxy-9-
~, oxo-16,17,18,19,20-penatnor-5-cis,13-trans-prostadienoic
acid, RF = 0.2 and 0.3 (10% methanol in methylene chloride).
The n.m.r. spectrum of each epimer ~n deuterated acetone)
showed the following characteristic bands (~ values):-
7.25-7.45, 4 aromatic protons.
5.0-5.9, 8H, 4 olefinic protons, 3 exchangable
protons and PhC_(OH).CH=CH-
4 1, lH, 11~ proton.
The mass spectrum of the bis-trimethylsil~l-g-
methoxime meth~l ester showed M =579.2603, calculated for
C29H46ClN05Si2 = 579.2603. The 9-oxo-bis-ester used
3~
- ~6 -
, , .
.
.- -.
-
104200Z
as starting material may be prepared as follows:-
To a solution of 4~-[3-(4-chlorophenyl)-2,3,3a~,
6a~-tetrahydro-3-hydroxy-1-trans-propenyll-5~-hydroxy-2-
oxocyclopenteno[b~furan (165mg.) in methylene chloride
(5 ml.) under an atmosphere of nitrogen were added
successively redistilled 2-methoxypropene (0.45 ml.) and
a solution of anhydrous toluene-p-sulphonic acid in
tetrahydrofuran (0.2ml. of a 1% solution). After 25 mins.,
pyridine (2 drops) was added, followed by ethyl acetate
(30 ml.). The solution was washed successively with
saturated sodium bicarbonate and saturated brine, and was
dried Evaporation of the solvents gave a mixture of
epimeric l-methoxy-l-methylethyl ethers, as a clear oil,
RF = 3 and 0.4 (25% ethyl acetate in toluene).
To a solution of the epimeric ether (228mg.)
in dry tGluene (lOml.) under an atmosphere of nitrogen at
-78C., was added 0.4 ml. of a 1.96 m mole/ml. solution of
di-isobutyl aluminium hydride in toluene. After 30 mins.,
the reaction was quenched by the dropwise addition of
methanol(2 ml.), and after a further 15 minutes at room
temperature, a mixture of 1:1 saturated brine/water (15 ml.)
was added, and the mixture was extracted with ethylacetate
(3 x 25 ml.). The extract was washed with saturated brine
and dried, and the solvents were evaporated to give a
mixture of epimers of the lactol, 4~-[3-(4-chlorophenyl)-3-
~ 3~
., .
- . .. ~ -.. . ~ ....... ~ . . . . - .
~ ~ . .. . . ~ .
lO~Z002
(l-methoxy-l-methylethoxy)-l-trans-propenylJ-2,3,3aB,6a~-
tetrahydro-2~-hydroxy-5~-~-methoxy-1-methylethoxy)-
cyclopenteno[b~furan, RF = -3 (1:1 ethyl acetate/toluene).
A solution of the lactol (243mg.) in dimethyl
sulphoxide (5 ml.) was added to a solution of sodium
5-triphenylpilophoranylidene va1era'e prepared
from 1 mole of (4-carboxybutyl)triphenyl phosphonium
bromide with 2 moles of methane sulphinyl methyl sodium
in dimethyl sulphoxide. The solution was stirred for
1 hour, and the solvent was removed by evaporation under
reduced pressure. The residue was shaken with water
(5 ml.) and ether (3 ml.), the aqueous layer was separated
and extracted with ether (4 x 3 ml.) and the extracts
were discarded. The aqueous solution was acidified to
pH 5.5 with oxalic acid and extracted with a mixture
of equal parts of ether and petroleum ether (b.p. 40-60C.)
(6 x 4 ml.). The combined extracts were washed with
saturated brine and dried, and evaporation of the solvents
gave 15-(4-chlorophenyl)-9~-hvdroxy-11~,15-bis-(1-methoxy-1-
methylethoxy)-16,17,18,19,20-pentanor-5-cis,13-trans-
prostadienoic acid. RF = 5 (20% methanol in methylene
chloride).
A solution of this prostadienoic acid derivative
(98mg.) in methylene chloride (1 ml.) was added to a
stirred solution of chromium trioxide (145 mg.) in
..,
: ,
i ' ~:
10~2Q02
methylene chloride (3 ml.). After 15 minutes at room
temperature the mixture was extracted with ether (2 x 10 ml.),
and the extracts were washed with saturated brine and
dried. Evaporation of the solvents give the required
5 9-oxo-bis-ether, RF ~ 0.6 (10% methanol in methylene
chloride).
Example 9
% w/v
15-(4-trifluromethylphenyl)-9a,11a,15-
trihydroxy-16,17,18,19,20-pentanor-5-
cis,13-trans-prostadienoic acid 0.1
Sodium phosphate 2.9
Sodium hydrogen phosphate 0.3
Water for injection to 100
The sodium phosphate was dissolved in about
80% of the water, followed by the prostadienoic acid
derivative, and, when dissolved, the sodium hydrogen
phosphate. The solution was made up to volume with
water for injection, and the pH was checked to be between
6,7 and 7,7. The solution was filtered to remove
particulate matter, sterilised by filtration, and filled
into presterilised neutral glass ampoules under aseptic
conditions.
The prostadienoic acid derivative may, of course,
be replaced by an equivalent amount of another prostanoic
acid derivative of the invention.
..
~ . . , . ; . . . . .
.. . . - .. i . :
- . .. . . .
.
.. . . .. . .
